During the cardiac remodeling that precedes heart failure (HF), multiple biomolecules (e.g., nucleic acids and proteins) are simultaneously shifting towards new steady state as the heart undergoes massive and progression changes in cell state. Systems technology now allows the molecular profiles of multiple biomolecules to be simultaneously measured, but results are often difficult to interpret due to the poor correlation between mRNA and protein abundance, in part because the synthesis and degradation rates of protein molecules are unaccounted for. Recent findings from our group suggest that cardiac remodeling is characterized by widespread remodeling in protein turnover dynamics, especially in nuclear proteins. Protein turnover rate correlates well with phenotypic changes whilst being largely orthogonal from protein abundance, highlighting that it is a missing dimension to our understanding of biological regulation of cardiac remodeling. We postulate that a class of heretofore unexplored disease drivers exists in the cardiac nuclei whose decreased turnover due to impaired proteolysis drives the pathogenic process of cardiac remodeling. To test this hypothesis, we designed three specific aims. Aim 1 will utilize a technological platform we recently developed to measure RNA abundance, protein abundance, and protein turnover in combination in vivo. We will search for candidate protein drivers that exhibit decreased/unchanged mRNA expression, decreased/unchanged protein turnover, but increased abundance, suggesting impaired proteolysis. Furthermore, we will (i) utilize a systems genetic model to contrast mouse strains that are susceptible vs. resistant to a well-characterized model of cardiac remodeling (isoproterenol challenge); and (ii) prioritize molecular features that are restored during reverse remodeling following isoproterenol withdrawal. Aim 2 will validate the candidate drivers by examining their mechanism of proteolysis and susceptibility to proteasomal degradation in vitro. Aim 3 will validate the disease proteins using in vitro models and in human NYHA Class IV HF patients and HF patients with LVAD-mediated reverse remodeling to ensure the discovered protein drivers are translationally relevant. We expect the experiments to shed light on the role of proteolysis in cardiac remodeling and disease susceptibility.